Abstract 10887: Identification of Upstream Regulatory Mechanisms of Semaphorin 3c Signaling During the Development of the Outflow Tract
A genetic interaction of two progenitor cell lineages, the cardiac neural crest (CNC) and the second heart field (SHF), play key roles in development of the cardiac outflow tract (OFT). CNC migrate into the OFT derived from the SHF and form the aorto-pulmonary septum. Recently, we showed that GATA6 directly regulated the Semaphorin 3C (SEMA3C) signaling essential for interaction between CNC and SHF during the development of the OFT. In order to further clarify mechanisms underlying the regulation of SEMA3C signaling, we delineated the enhancer of Sema3c and identified conserved regulatory elements for Srf, Fox and Sox factors in the 5’UTR region, and for T-box factors in the 3’UTR region, respectively. Srf, Foxc1, Foxc2, Sox4 and Tbx1 have been shown to play essential roles in the OFT development. Interestingly, Srf, Foxc1, Foxc2 and Sox4 activated Sema3c through direct bindings to their regulatory elements, whereas Tbx1 negatively regulated the transactivation of Sema3c by Gata6, probably via its direct binding to the regulatory elements on the 3’UTR sequence of Sema3c in vitro. Consistent with these results, in transgenic mice harboring the lacZ reporter under control of the enhancer including Gata6 and Tbx1 regulatory elements of Sema3c, the lacZ expression was ectopically expanded to whole pharyngeal mesenchyme in mice with Tbx1 hypomorphic alleles, while it was normally restricted to the SHF in the pharyngeal mesoderm of wild-type mice. Our data suggest a novel molecular mechanism underlying the differentiation of OFT progenitor cells where Tbx1 may restrict the Sema3c expression to progenitor cells in the SHF, and Gata6, Srf, Foxc1/c2 and Sox4 may activate the Sema3c expression in these cells in a process of differentiation into the OFT myocardium, eventually leading to a proper signal for the CNC migration into the OFT.
- © 2011 by American Heart Association, Inc.